Method for inhibition of erythrocyte aggregation using anellated tricyclic compounds

Abstract

The present invention is concerned with the use of compounds of the general formula: <IMAGE> (I) wherein R1 is a phenyl radical of the general formula: <IMAGE> or R1 is a 5 or 6 membered heterocycle or when X is a valency bond R1 is also H, OH, mercapto, amino, alkyl, alkenyl, alkynyl, haloalkyl, alkylthio, formylaminoalkyl, pyridylcarbonylamino, cycloalkyl, or cycloalkenyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl or hydroxyalkyl of claim 1 or 2 for the preparation of pharmaceutical compositions with an erythrocyte aggregation inhibition action useful, for example, in states of shock or circulatory disturbance.

What is claimed: 
     
       1. A method for the inhibition of erythrocyte aggregation which comprises treating patients with conditions having need of such inhibition with an effective amount of a compound of the formula: ##STR8## wherein R 1  is a phenyl of the formula: ##STR9## wherein R 2 , R 3 , R 4 , which can be the same or different, are hydrogen, C 1  -C 5  alkanesulphonyloxy, trifluormethanesulphonyloxy, C 1  -C 5  alkanesulphonylamino, trifluorometanesulphonylamino, C 1  -C 5  N-alkyl-C 1  -C 5  -alkanesulphonylamino, C 1  -C 5  N-alkyl-trifluoromethanesulphonylamino, C 1  -C 5  alky.lsulphenylmethyl, C 1  -C 5  alkylsulphinylmethyl, C 1  -C 5  alkylsulphonylmethyl or, carbonyl groups substituted by hydroxyl C 1  -C 5  -alkoxy amino C 1  -C 5  -alkylamino, di-C 1  -C 5  -alkylamino, or   sulphonyl groups substituted by amino, C 1  -C 5  -alkylamino, di-C 1  -C 5  -alkylamino or cyclic imino, wherein a methylene group in the 4-position of the cyclic imino can be replaced by a sulphur or oxygen atom, or C 1  -C 5  alkyl-carbonylamino, amino-carbonylamino, C 1  -C 5  -alkyl-aminocarbonylamino, C 1  -C 5  -alkylthio, C 1  -C 5  -alkylsulphinyl, C 1  -C 5  -alkylsulphonyl, or   halogen, nitro, cyano, amino, hydroxyl, C 1  -C 5  -alkoxy, C 1  -C 5  -alkyl, C 2  -C 5  -alkenyloxy, C 2  -C 5  -alkynyloxy, cyano-C 1  -C 5  alkoxy, carboxy-C 1  -C 5  -alkoxy, C 1  -C 5  -alkoxycarbonyl-C 1  -C 5  alkoxy, di-C 1  -C 5  -alkylamino, 1-imidazolyl, trifluoromethyl; or   R 1  is a heterocyclic five-membered ring containing up to 4 heteroatoms, or heterocyclic six-membered rings containing up to 5 heteroatoms, wherein the heteroatoms in the 5- or 6-membered ring can be the same or different and are oxygen, sulphur or nitrogen atoms and, can carry an oxygen atom on one or more nitrogen, atoms, and the five- and six-membered rings can be unsubstituted or substituted at least once by C 1  -C 6  -alkyl, C 1  -C 6  -alkoxy, C 1  -C 6  -alkylthio, hydroxyl, nitro, amino, halogen or cyano; or when   X represents a valency bond, besides the above-mentioned groups, R 1  can also be hydrogen, hydroxyl, mercapto amino or C 1  -C 8  -alkyl, C 3  -C 6  -cycloalkenyl, C 2  -C 8  -alkenyl, C 3  -C 6  -cyclo-alkenyl, C 2  -C 8  alkynyl, C 1  -C 8  -haloalkyl, C 1  -C 8  hydroxyalkyl, C 1  -C 8  alkoxyalkyl, C 1  -C 8  carboxyalkyl, C 1  -C 8  alkoxycarbonyl C 1  -C 8  -alkyl, C 1  -C 8  -alkylthio, formylamino-C 1  -C 8  -alkyl or pyridylcarbonylamino,   X is a valency bond or an C 1  -C 8  alkylene or vinylene,   A is nitrogen or--CR 5  wherein R 5  is hydrogen, cyano, C 1  -C 7  -alkyl, C 2  -C 7  alkenyl, C 3  -C 7  cycloalkyl, C 3  -C 7  -cycloalkenyl, C 1  -C 7  -alkylcarbonyl, C 1  -C 7  -alkoxycarbonyl, carboxyl, aminocarbonyl, C 1  -C 7  -alkylaminocarbonyl, di-C 1  -C 7  -alkylaminocarbonyl or aryl,   B is oxygen, sulphur or═NR 6  wherein R 6  is hydrogen or C 2  -C 6  -alkyl, or B is═CR 7  R 8 , wherein R 7  is hydrogen, C 1  -C 6  -alkyl, C 2  -C 6  -alkenyl or C 3  -C 7  -cycloalkyl and   R 8  is hydrogen, cyano, C 1  -C 6  -alkyl, C 2  -C 6  -alkenyl or a carbonyl substituted by hydroxyl, C 1  -C 6  -alkyl C 1  -C 6  -alkoxy amino, C 1  -C 6  -alkylamino, di-C 1  -C 6  -alkylamino or hydrazino, or R 7  and R 8  together form an C 1  -C 6  -alkylidene or C 3  -C 7  -cycloalkyliden, or R 7  and R 8 , together with the carbon atom to which they are attached, form a C 3  -C 7  -spirocycle; and   the tautomers, optically-active forms and racemic mixtures thereof and the physiologically acceptable salts thereof with inorganic and organic acids in a pharmaceutically acceptable carrier.   
     
     
       2. The method of claim 1, comprising treating said conditions with a pharmaceutically effective amount of a compound of Formula I wherein R 1  is a phenyl radical of formula (II) wherein R 2  is hydrogen, halogen, cyano, nitro, amino or a methanesulphonyloxy, trifluoromethanesulphonyloxy, methanesulphonylamino, trifluoromethanesulphonylamino, methanesulphonylmethylamino, trifluoromethanesulphonylmethylamino, methylsulphinylmethyl, methylsulphonylmethyl, aminocarbonyl, aminosulphonyl, methylaminosulphonyl, dimethylaminosulphonyl, acetylamino, methylthio, methylsulphinyl, methylsulphonyl, hydroxyl, allyloxy, methyl, methoxy, propargyloxy, cyanomethoxy, methoxycarbonylmethoxy, dimethylamino, trifluoromethyl or 1-imidazolyl, R 3  is hydrogen, chlorine, hydroxyl, methyl, methoxy or dimethylamino, and   R 4  is hydrogen or methoxy; or   R 1  is pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isothiazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, thiadiazolyl, isoxazolyl, oxadiazolyl, pyridinyl, N-oxypyridinyl, pyrazinyl, pyrimidinyl, N,N'-dioxypyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, triazinyl, tetrazinyl or a methyl-, ethyl-, methoxy-, ethoxy-, methylthio-, ethylthio-, or chloro-substituted derivative thereof or,   when X is a valency bond, besides the above-mentioned groups R 1  is hydrogen, hydroxyl, mercapto, amino, methyl, ethyl, propyl, butyl, pentyl, hexyl, vinyl propenyl, propynyl, cyclopentenyl, cyclohexyl, trifluoromethyl or methylthio,   X is a valency bond, ethylene or vinylene,   A is nitrogen or--CH,   B is oxygen, sulphur or═NR 6 , wherein R 6  is methyl, ethyl or propyl, or B is═CR 7  R 8 , wherein R 7  is hydrogen or methyl and R 8  is methyl, ethyl or isopropyl, or   R 7  or R 8 , together with the carbon atom to which they are attached, form a spirocyclopentyl ring.   
     
     
       3. The method of claim 1 or claim 2 comprising treating said conditions with a pharmaceutically effective amount of a compound of Formula I wherein when R 1  is Formula II then R 2 , R 3  and R 4  are methanesulphonyloxy, ethanesulphonyloxy, n-propanesulphonyloxy, isopropanesulphonyloxy, trifluoromethanesulphonyloxy, methylsulphenylmethyl, ethylsulphenylmethyl, n-propylsulphenylmethyl, methylsulphinylmethyl, ethylsulphinylmethyl, n-propylsulphinylmethyl, methylsulphonylmethyl, ethylsulphonylmethyl, n-propylsulphonylmethyl, methanesulphonylamino, ethanesulphonylamino, n-propanesulphonylamino, trifluoromethanesulphonylamino, N-methyl-methanesulphonylamino, N-ethylmethanesulphonylamino, N-methyl-ethanesulphonylamino, N-ethylethanesulphonylamino, N-isopropylethanesulphonylamino, N-methyl-n-propanesulphonylamino, N-n-propyl-propanesul-phonylamino, N-methyltrifluoromethanesulphonylamino, N-ethyltrifluoromethanesulphonylamino, N-isopropyl-trifluoromethanesulphonylamino, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, methylaminocarbonyl, ethylaminocarbonyl, dimethylaminocarbonyl, di-n-propylaminocarbonyl, N-methyl-ethylaminocarbonyl, trifluoromethyl, methylaminosulphonyl, ethylaminosulphonyl, n-propylaminosulphonyl, n-butyl aminosulphonyl, n-pentylaminosulphonyl, dimethylaminosulphonyl, diethylaminosulphonyl, di-n-propylaminosulphonyl, N-methyl-isopropylaminosulphonyl, acetylamino, propionylamino, methylcarbonylamino, ethylaminocarbonylamino and propylaminocarbonylamino, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, allyloxy, but-2-enyloxy, but-3-enyloxy, pent-2enyloxy, propargyloxy, but-2-ynyloxy, but-3-ynyloxy, cyanomethoxy, cyanoethoxy, methoxycarbonylmethoxy, methoxycarbonylethoxy, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, methylsulphonyl and ethylsulphonyl; and wherein the sulphonyl groups substituted by cyclic amino are selected from the group consisting of morpholino, thiomorpholino, pyrrolidino, piperidino and hexamethyleneiminosulphonyl.   
     
     
       4. The method of claim 1 or claim 2 comprising treating said conditions with a compound of formula I wherein R 1  is a phenyl of formula II and wherein the monosubstituted phenyl compounds are hydroxy-, C 1  -C 3  -alkyl-, C 1  -C 3  -alkoxy-, allyloxy-, propargyloxy-, cyanomethoxy-, methoxycarbonylmethoxy-, halo-, nitro-, cyano-, aminocarbonyl-, methoxycarbonyl-, amino-, C 1  -C 3  -dialkylamino-, C 1  -C 3  -alkylthio-, C 1  -C 3  -alkyl-sulphinyl- , C 1  -C 3  -alkylsulphonyl-, C 1  -C 3  -alkylsulphonyloxy- and 1-imidazolyl-phenyls, wherein the substitutent is in the 2-, 3- or 4-position, and disubstituted phenyls are C 1  -C 3  alkanesulphonyloxy, trifluoromethylsulphonyloxy, C 1  -C 3  alkylsulphenylmethyl, C 1  -C 3  alkylsulphinylmethyl, C 1  -C 3  alkylsulphonylmethyl, C 1  -C 3  alkylsulphonylamino, C 1  -C 3  N-alkyl-alkylsulphonylamino, trifluoromethylsulphonylamino, N-alkyl-trifluoromethylsulphonylamino, or carbonyl groups substituted by hydroxy, alkoxy, amino, C 1  -C 3  alkylamino or C 1  -C 3  dialkylamino or sulphonyl substituted by amino, C 1  -C 3  dialkylamino or morpholino, C 1  -C 3  alkylaminosulphonyl, C 1  -C 3  alkylcarbonylamino carbonylamino, aminocarbonylamino or N-alkyl -aminocarbonylamino, halogen, hydroxyl, cyano, nitro or amino C 1  -C 3  alkyl, C 1  -C 3  alkoxy allyloxy, propargyloxy, cyanomethoxy, methoxycarbonylmethoxy, C 1  --C 3  dialkylamino, C 1  -C 3  alkylthio, C 1  -C 3  alkylsulphonyl, C 1  -C 3  alkylsulphonyl or 1-imidazolyl radicals, in which the two substituents can be the same or different and can be in the 2,3-, 2,4- 2,5-, 2,6-, 3,4- and 3,5- positions, and trisubstituted phenyls comprise hydroxyl and methoxy substituents.   
     
     
       5. The method of claim 4 wherein the disubstituted phenyl is in the 2,4-, 2,5- or 3,4-position. 
     
     
       6. The method of claim 1 or claim 2 comprising treating said conditions with a compound of Formula I wherein R 1  is pyrrole, furan, thiophene, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, triazole, tetrazole, thiadiazole, oxadiazole, pyrazine, N,N'-dioxypyrazine, pyrimidine, N,N'-dioxypyrimidine, pyridazine, oxazine, thiazine, triazine, tetrazine, pyridine or N-oxypyridine, and wherein the above ring is unsubstituted or wherein the substituents thereon are methyl, ethyl, methoxy, ethoxy, methylthio and ethylthio. 
     
     
       7. The method of claim 1 or claim 2 comprising treating said conditions with a compound of Formula I wherein X is a valency bond or methylene, ethylene or vinylene, and when X is a valency bond, R 1 , is methyl, ethyl, propyl, butyl, pentyl, hexyl, vinyl, propenyl or propynyl, or   R 1  is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl or cyclohexenyl, or   R 1  is ethoxymethyl, methoxyethyl, ethoxyethyl, carboxymethyl, carboxypropyl, carboxybutyl, methoxycarbonylmethyl, methoxycarbonylethyl, methoxycarbonylpropyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, ethoxycarbonylpropyl, propoxycarbonylethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl or hydroxybutyl, and A is nitrogen or -C-R 5  wherein R 5  is acetyl, propionyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl or.dimethylaminocarbonyl, and   B is=NR 6  wherein R 6  is methyl, ethyl, propyl, isopropyl, butyl, 2-butyl or 1,1-dimethylethyl, or B is═CR 7  R 8  wherein R 7  is H, methyl, ethyl, isopropyl, 3-pentyl, cyclopentyl or cyclohexyl and R 8  is hydrogen, cyano, carboxyl or methyl, ethyl, isopropyl, 3-pentyl, acetyl, propynyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl or hydrazinocarbonyl, or   R 7  and R 8  together with the carbon atom to which they are attached form a spirocyclopropyl, spirocyclobutyl, spirocyclopentyl or spirocyclohexyl ring or   R 7  and R 8  together form an isopropylidene or cyclohexylidine ring   
     
     
       8. The method of claim 1 or 2 comprising treating said conditions with a compound of formula I wherein R 1  is a phenyl of formula II wherein R 2 , R 3 , R 4  is hydrogen, hydroxy chlorine C 1  -C 5  -alkyl, C 1  -C 5  -alkoxy, C 2  -C 5  -alkoxyloxy or trifluoromethyl. 
     
     
       9. The method of claim 1 comprising treating said conditions with a compound of formula I wherein A is nitrogen and B is═CR 7  R 8  wherein R 7  or R 8  are hydrogen C 1  -C 6  -alkyl or together form a C 3  -C 7  spirocycle. 
     
     
       10. A method for the inhibition of erythrocyte aggregation which comprises treating patients having conditions with need of such inhibition with an effective amount of at least one compound selected from the group consisting of 7,7-dimethyl-2-(2-thienyl) -6, 7-dihydro-3H, 5H -pyrrolo -benzimidazol-6-one   7,7-dimethyl-2-(3,4-dichlorophenyl) -6,7-dihydro-3H,5H-pyrrolo benzimidazol-6-one,   7,7-dimethyl-2-(4-trifluoromethylphenyl) -6,7-dihydro-3H,5H-pyrrolo benzimidazol-6-one,   ' -phenyl-spiro -6'-one, and   2'-(4-methoxyphenyl)-spiro -6'-one or a physiologically acceptable salt thereof in a pharmaceutically acceptable carrier.     
     
     
       11. the method of calim 1, 2, 9 or 10 comprising treating said conditions with an amount of from 10 to 2,000 mg per day per body weight of 75 kg.